A two-hit model for developmental defects in Gorlin syndrome

Levanat, Sonja; Gorlin, Robert J.; Fallet, Shari; Johnson, Dennis R.; Fantasia, John E; Bale, A.E.

doi:10.1038/ng0196-85

Cited by 176 publications

(127 citation statements)

References 12 publications

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“…Until then, the true importance of the Gorlin syndrome gene in sporadic medulloblastoma will remain conjecture. Recently LOH has been shown to be the mechanism for the development of the typical jaw cysts in Gorlin syndrome (Levanet et al, 1996). We were unable to confirm this as a mechanism for the development of a cataract in an affected family member.…”

Section: Discussioncontrasting

confidence: 56%

The gene for the naevoid basal cell carcinoma syndrome acts as a tumour-suppressor gene in medulloblastoma

Cowan

Hoban²,

Kelsey³

et al. 1997

Br J Cancer

116

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Summary Individuals with naevoid basal cell carcinoma (Gorlin) syndrome are at increased risk of developing medulloblastoma in childhood. We have shown that approximately 5% of patients with Gorlin syndrome will develop this complication in the first few years of life, and in addition 10% of patients with medulloblastoma diagnosed at age 2 years or under have Gorlin syndrome. One out of three medulloblastomas occurring in patients with Gorlin syndrome was shown to have lost the wild-type allele on 9q, indicating that the Gorlin locus probably acts as a tumour suppressor in the development of this tumour. We have also confirmed this role in a basal cell carcinoma (BCC) from the same individual. Information from these families would suggest that Gorlin syndrome is more common than previously recognized and may not always be diagnosed on clinical grounds alone even in middle life.

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Section: Discussioncontrasting

confidence: 56%

The gene for the naevoid basal cell carcinoma syndrome acts as a tumour-suppressor gene in medulloblastoma

Cowan

Hoban²,

Kelsey³

et al. 1997

Br J Cancer

116

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“…49,58 The gene, Patched, which modifies the Hedgehog signaling pathway, is mutated not only in the syndrome but in ordinary isolated basal cell carcinomas. 59,60 Patched, in the absence of its ligand, Sonic Hedgehog, acts a cell-cycle regulator, normally inhibiting expression of downstream genes (Smoothened, among others), which control cell fate, patterning, and growth 61 (Fig.…”

Section: Geneticsmentioning

confidence: 99%

Nevoid basal cell carcinoma (Gorlin) syndrome

Gorlin

2004

Genetics in Medicine

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323

191

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“…20 The PTCH1 gene is suggested to be a tumor suppressor, and inactivating germline mutations of PTCH1 cause basal cell nevus syndrome (BCNS) (MIM 109400). 21,22 BCNS or Gorlin syndrome is an uncommon autosomal dominant inherited disorder, which is characterized by multiple skeletal, dental, ophthalmic, and neurological abnormalities, and predisposition for developing multiple basal cell carcinomas (BCC). 23 Most of the malformations are caused by PTCH1 haploinsufficiency, indicating that the physiological pathway activity is sensitive to relatively small changes in PTC1 levels.…”

Section: Introductionmentioning

confidence: 99%

Regulation of humanPTCH1bexpression by different 5' untranslated regioncis-regulatory elements

et al. 2015

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Inga (2015) Regulation of human PTCH1b expression by different 5' untranslated region cis-regulatory elements, RNA Biology, 12:3, 290-304, DOI: 10.1080/15476286.2015 PTCH1 gene codes for a 12-pass transmembrane receptor with a negative regulatory role in the Hedgehog-Gli signaling pathway. PTCH1 germline mutations cause Gorlin syndrome, a disorder characterized by developmental abnormalities and tumor susceptibility. The autosomal dominant inheritance, and the evidence for PTCH1 haploinsufficiency, suggests that fine-tuning systems of protein patched homolog 1 (PTC1) levels exist to properly regulate the pathway. Given the role of 5' untranslated region (5'UTR) in protein expression, our aim was to thoroughly explore cis-regulatory elements in the 5'UTR of PTCH1 transcript 1b. The (CGG) n polymorphism was the main potential regulatory element studied so far but with inconsistent results and no clear association between repeat number and disease risk. Using luciferase reporter constructs in human cell lines here we show that the number of CGG repeats has no strong impact on gene expression, both at mRNA and protein levels. We observed variability in the length of 5'UTR and changes in abundance of the associated transcripts after pathway activation. We show that upstream AUG codons (uAUGs) present only in longer 5'UTRs could negatively regulate the amount of PTC1 isoform L (PTC1-L). The existence of an internal ribosome entry site (IRES) observed using different approaches and mapped in the region comprising the CGG repeats, would counteract the effect of the uAUGs and enable synthesis of PTC1-L under stressful conditions, such as during hypoxia. Higher relative translation efficiency of PTCH1b mRNA in HEK 293T cultured hypoxia was observed by polysomal profiling and Western blot analyses. All our results point to an exceptionally complex and so far unexplored role of 5'UTR PTCH1b cis-element features in the regulation of the Hedgehog-Gli signaling pathway.

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A two-hit model for developmental defects in Gorlin syndrome

Cited by 176 publications

References 12 publications

The gene for the naevoid basal cell carcinoma syndrome acts as a tumour-suppressor gene in medulloblastoma

The gene for the naevoid basal cell carcinoma syndrome acts as a tumour-suppressor gene in medulloblastoma

Nevoid basal cell carcinoma (Gorlin) syndrome

Regulation of humanPTCH1bexpression by different 5' untranslated regioncis-regulatory elements

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